CN107412780B - Antibacterial agent based on gold nanoparticle surface modified nitrogen heterocyclic micromolecules - Google Patents

Antibacterial agent based on gold nanoparticle surface modified nitrogen heterocyclic micromolecules Download PDF

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CN107412780B
CN107412780B CN201610345068.2A CN201610345068A CN107412780B CN 107412780 B CN107412780 B CN 107412780B CN 201610345068 A CN201610345068 A CN 201610345068A CN 107412780 B CN107412780 B CN 107412780B
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CN107412780A (en
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蒋兴宇
冯艳
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National Center for Nanosccience and Technology China
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
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    • C09K11/08—Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials
    • C09K11/58—Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials containing copper, silver or gold
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    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention provides a gold nanoparticle, wherein the surface of the gold nanoparticle is modified with nitrogen heterocyclic small molecules, and the gold nanoparticle can be preferably selected from one or more of triazole with sulfhydryl, imidazole with sulfhydryl, purine with sulfhydryl and benzothiazole with sulfhydryl. The gold nanoparticles prepared by the method have good antibacterial property to gram-negative bacteria, gram-positive bacteria and/or clinical isolates with multi-drug resistance, and can have good biocompatibility. The invention also provides a preparation method of the gold nanoparticle, an antibacterial composition containing the gold nanoparticle, a kit and application of the gold nanoparticle and the antibacterial composition in preparation of antibacterial products or medicines.

Description

Antibacterial agent based on gold nanoparticle surface modified nitrogen heterocyclic micromolecules
Technical Field
The invention relates to a gold nanoparticle, in particular to a gold nanoparticle with a surface modified with nitrogen heterocyclic micromolecules, a preparation method of the gold nanoparticle, an antibacterial composition containing the gold nanoparticle, a kit and application of the gold nanoparticle and the antibacterial composition in preparation of antibacterial products or medicines.
Background
Bacterial infections are one of the most major causes of human health threats, but the abuse of traditional antibiotics based on small organic molecules has led to the emergence of super-resistant bacteria. Bacterial resistance has led to a serious morbidity and mortality, especially in hospital-related infections, with a corresponding increase in public health costs. Thus, there is a need to invent new effective antibacterial agents, especially against super-resistant bacteria.
Nanomaterials show their potential antimicrobial properties due to their large specific surface area, flexible surface functionalization and inherent physicochemical properties. Nano silver, nano copper, nano zinc oxide, carbon nano tubes and the like all show certain antibacterial activity, but the materials cannot be used as ideal antibacterial agents due to the toxicity and poor antibacterial performance of the nano silver, the nano copper, the nano zinc oxide, the carbon nano tubes and the like. Gold nanoparticles have good biocompatibility and mature synthetic method, so that the gold nanoparticles are more and more paid attention to as antibacterial agents. Many studies show that the gold nanoparticles have no antibacterial activity, but the gold nanoparticles modified by thiol, amine and phosphorus compounds can be used as antibacterial drugs. Compared with antibiotics, the antibiotic modified gold nanoparticles have obviously enhanced antibacterial activity, but the gold nanoparticles still have no effect on drug-resistant bacteria.
In order to synthesize effective gold nanoparticles with antibacterial activity, the applicant has invented a series of gold nanoparticles modified by mercaptopyrimidine with antibacterial activity, which have good antibacterial effects on gram-negative bacteria, gram-positive bacteria and super-drug-resistant bacteria, but have some serious disadvantages, for example, two small molecular ligands are required to simultaneously modify the gold nanoparticles, and functionalization of different effects of the two ligands seriously affects the repeatability and antibacterial effect of the experiment.
Therefore, new gold nanoparticles with good repeatability, high antibacterial activity and simplified ligand modification need to be discovered and researched.
Disclosure of Invention
Therefore, in order to overcome the defects of the prior art, the invention provides a gold nanoparticle with a surface modified with nitrogen heterocyclic micromolecules, a preparation method of the gold nanoparticle, an antibacterial composition containing the gold nanoparticle, a kit and application of the gold nanoparticle and the antibacterial composition in preparation of antibacterial products or medicines.
In order to achieve the above object, a first aspect of the present invention provides a gold nanoparticle, wherein the surface of the gold nanoparticle is modified with small nitrogen heterocyclic molecules.
The gold nanoparticle according to the first aspect of the present invention, wherein the nitrogen-heterocycle small molecule has a mercapto group. Preferably, the nitrogen heterocyclic small molecule is selected from one or more of triazole with sulfhydryl, imidazole with sulfhydryl, purine with sulfhydryl and benzothiazole with sulfhydryl. More preferably, the azacyclo small molecule is selected from one or more of 3-amino-5-mercapto-1, 2, 4-triazole (ATT), 4-amino-3-hydrazine-5-mercapto-1, 2, 4-triazocene (AHMT), 2-Mercaptoimidazole (MI), methimazole (MTM), 2-amino-6-mercaptopurine (AMP) and 6-amino-2-mercaptobenzothiazole (AMBT).
Different from pyrimidine molecules adopted in the prior art, the nitrogen heterocyclic micromolecules have five-membered ring structures, have certain biological activity, have antibacterial effects on gram-negative bacteria and gram-positive bacteria after the gold nanoparticles are modified, and have good antibacterial effects.
In one embodiment, the surface of the gold nanoparticle is modified with only one thiol-group-containing small nitrogen heterocyclic molecule. The invention provides six preferable nitrogen heterocyclic micromolecules with sulfydryl, which are respectively two triazoles (ATT and AHMT), two imidazoles (MI and MTM), one purine (AMP) and one benzothiazole (AMBT), wherein each nitrogen heterocyclic micromolecule can be used for independently modifying gold nanoparticles and can obtain good antibacterial activity.
Wherein, the chemical structural formula of the 3-amino-5-mercapto-1, 2, 4-triazole (ATT) is as follows:
Figure BDA0000997007500000021
the chemical structural formula of the 4-amino-3-hydrazine-5-mercapto-1, 2, 4-triazocene (AHMT) is as follows:
Figure BDA0000997007500000031
the chemical structure of 2-Mercaptoimidazole (MI) is:
Figure BDA0000997007500000032
the chemical structural formula of methylthioimidazole (MTM) is:
Figure BDA0000997007500000033
the chemical structural formula of 2-amino-6-mercaptopurine (AMP) is:
Figure BDA0000997007500000034
the chemical structural formula of the 6-amino-2-mercaptobenzothiazole (AMBT) is as follows:
Figure BDA0000997007500000035
the gold nanoparticle according to the first aspect of the present invention, wherein a molar ratio of the nitrogen heterocyclic small molecule to the gold element in the gold nanoparticle is 0.1-0.99: 1. Preferably 0.22-0.92: 1. And/or the average particle size of the gold nanoparticles is 1-35 nm. Preferably 2 to 10 nm.
A second aspect of the present invention provides a production method for producing the gold nanoparticle of the first aspect of the present invention, the production method comprising:
(1) dissolving the small nitrogen heterocyclic molecules in methanol (MeOH) and then reacting with chloroauric acid (HAuCl)4) Mixing to form a mixed solution;
(2) adding a reducing agent into the mixed solution obtained in the step (1), and fully reacting to obtain a gold nanoparticle crude product;
(3) and (3) purifying the gold nanoparticle crude product in the step (2) to obtain the gold nanoparticles.
Preferably, the molar ratio of the nitrogen heterocyclic small molecule to the chloroauric acid in the step (1) is 1-10: 1, and most preferably 10: 1.
The preparation method according to the second aspect of the present invention, wherein, after the mixing in step (1), the mixed solution is stirred and added with a nonionic surfactant under ice bath conditions to be uniformly mixed. Preferably, the non-ionic surfactant is selected from one or more of Triton X-100, tween or polyethylene glycol, most preferably tween 80. And/or preferably, the molar ratio of the nonionic surfactant to the chloroauric acid is 0.1-2: 1, more preferably 0.5-1.5: 1. Among them, a magnetic stirrer may be used for stirring.
The production method according to the second aspect of the present invention, wherein the reducing agent in step (2) is selected from sodium borohydride (NaBH)4) Sodium ascorbate and sodium citrate, most preferably sodium borohydride. The reducing agent and the chloroauric acidThe molar ratio of the acid is 1 to 10:1, preferably 2 to 8:1, and most preferably 3: 1. And/or the reaction is carried out in an ice bath with stirring. The reaction time is preferably from 30 minutes to 2 hours, most preferably 1 hour.
The production method according to the second aspect of the invention, wherein the purification in the step (3) includes removing methanol. The removal of methanol is preferably carried out by means of a rotary evaporator. Preferably, the purification further comprises dialysis. More preferably, the dialysis is performed in a 14KD dialysis bag for 48 hours. And/or more preferably, distilled water is added to the gold nanoparticles from which methanol is removed to dissolve them, followed by dialysis.
In an embodiment, the gold nanoparticles are prepared by using a sodium borohydride reduction method under an ice bath condition, and synthesizing different nitrogen heterocycle modified gold nanoparticles by adjusting a molar ratio of the nitrogen heterocycle micromolecules to the chloroauric acid, wherein the molar ratio of the nitrogen heterocycle micromolecules to the gold element in the gold nanoparticles is 0.1-0.99: 1, preferably 0.22-0.92: 1. Specifically, the preparation method of the gold nanoparticle may include:
(1) respectively and completely dissolving different nitrogen heterocyclic micromolecules in methanol, and mixing the obtained solution with chloroauric acid to form a mixed solution, wherein the molar ratio of the nitrogen heterocyclic micromolecules to the chloroauric acid is 1-10: 1, and the most preferable ratio is 10: 1;
(2) stirring the mixed solution in the step (1) under an ice-bath magnetic stirrer, adding Tween 80, fully mixing and dissolving, adding sodium borohydride, wherein the molar ratio of the sodium borohydride to the chloroauric acid is 1-10: 1, preferably 2-8: 1, and most preferably 3:1, and continuously stirring for 1 hour to obtain gold nanoparticles (crude products);
(3) removing methanol by a rotary evaporator, adding a certain amount of distilled water to redissolve the gold nanoparticles, dialyzing the gold nanoparticles for 48 hours by using a dialysis bag with the density of 14KD, and collecting the gold nanoparticles and storing for later use.
In a third aspect of the present invention, there is provided an antibacterial composition comprising the gold nanoparticles of the first aspect of the present invention or gold nanoparticles prepared by the preparation method of the second aspect of the present invention. Preferably, the antimicrobial composition is an antimicrobial or an antimicrobial pharmaceutical composition. More preferably, the antibacterial agent or antibacterial pharmaceutical composition is resistant to one or more of the following bacterial species: gram-negative bacteria, gram-positive bacteria and clinical isolates with multidrug resistance. Further preferably, the gram-negative bacteria are selected from one or more of escherichia coli (e.coli), pseudomonas aeruginosa (p.aeruginosa) and klebsiella pneumoniae (k.pneumoniae), the gram-positive bacteria are selected from staphylococcus aureus (s.aureus), and/or the clinical isolates with multidrug resistance are selected from one or more of escherichia coli with multidrug resistance, pseudomonas aeruginosa with multidrug resistance and staphylococcus aureus with multidrug resistance. In one embodiment, the antibacterial pharmaceutical composition comprises a pharmaceutically acceptable carrier, and the gold nanoparticles of the first aspect of the present invention or the gold nanoparticles prepared by the preparation method of the second aspect of the present invention.
In a fourth aspect, the present invention provides a kit comprising gold nanoparticles of the first aspect of the invention or gold nanoparticles prepared by a method of the second aspect of the invention.
A fifth aspect of the present invention provides an application of the gold nanoparticles of the first aspect of the present invention, the gold nanoparticles prepared by the preparation method of the second aspect of the present invention, or the antibacterial composition of the third aspect of the present invention in preparing an antibacterial product or in preparing a medicament for preventing and/or treating a microorganism-caused disorder. Preferably, the antimicrobial product or medicament is resistant to one or more of the following bacterial species: one or more of gram negative bacteria, gram positive bacteria and clinical isolates with multidrug resistance. Wherein, the gram-negative bacteria are preferably selected from one or more of escherichia coli, pseudomonas aeruginosa and klebsiella pneumoniae, the gram-positive bacteria are preferably selected from staphylococcus aureus, and the clinical isolates with multidrug resistance are preferably selected from one or more of multidrug-resistant escherichia coli, multidrug-resistant pseudomonas aeruginosa and multidrug-resistant staphylococcus aureus. Preferably, the microbial-induced disorder is a disorder caused by one or more of gram-negative bacteria, gram-positive bacteria, and clinical isolates having multidrug resistance. Further preferably, the condition is selected from one or more of the following: skin and subcutaneous tissue infections, wound infections, otitis media, meningitis, peritonitis, enteritis, bronchitis, pneumonia, respiratory tract infections, urinary system infections, sepsis or sepsis.
A sixth aspect of the present invention provides a method of preventing and/or treating a microorganism-caused disorder, the method comprising administering to a subject a therapeutically effective amount of the gold nanoparticles of the first aspect of the present invention, the gold nanoparticles prepared using the preparation method of the second aspect of the present invention, or the antibacterial composition of the third aspect of the present invention. Preferably, the microbial caused condition may be a condition caused by gram bacteria and/or clinical isolates with multidrug resistance. More preferably, the condition may be selected from one or more of the following: skin and subcutaneous tissue infection, wound infection, otitis media, meningitis, peritonitis, enteritis, bronchitis, pneumonia, respiratory tract infection, urinary system infection, septicemia, sepsis, etc. The gram bacteria are gram-negative bacteria and gram-positive bacteria. Wherein, the gram-negative bacteria are preferably selected from one or more of escherichia coli, pseudomonas aeruginosa and klebsiella pneumoniae, the gram-positive bacteria are preferably selected from staphylococcus aureus, and the clinical isolates with multidrug resistance are preferably selected from one or more of multidrug-resistant escherichia coli, multidrug-resistant pseudomonas aeruginosa and multidrug-resistant staphylococcus aureus.
Wherein the administration can be by oral, injection, patch, spray, and other known techniques. The subject may be any animal, e.g., a human, having a condition as described above. The effective amount can include an amount effective to treat, reduce, alleviate, reduce, eliminate, or avoid one or more symptoms of a condition sought to be treated, or alternatively, the condition sought to be avoided, or otherwise produced a clinically identifiable beneficial change in the condition or its effect.
A seventh aspect of the present invention provides a gold nanoparticle for preventing and/or treating a microorganism-caused disorder, the gold nanoparticle being the gold nanoparticle of the first aspect of the present invention or the gold nanoparticle prepared according to the preparation method of the second aspect of the present invention.
Compared with the prior art, the prepared gold nanoparticles have good antibacterial property to gram-negative bacteria, gram-positive bacteria and/or clinical isolates with multi-drug resistance, and part of the prepared gold nanoparticles have good biocompatibility.
The invention synthesizes a series of gold nanoparticles with antibacterial effect by using a reduction method, which is used for sterilizing gram-negative bacteria, gram-positive bacteria and clinical isolates with multidrug resistance, thereby realizing the potential of the gold nanoparticles as an antibacterial agent. The micromolecular ligand (namely the azacyclo micromolecule) adopted by the invention has no antibacterial activity, and shows stronger antibacterial activity to gram-negative bacteria, gram-positive bacteria and even related clinical isolates with multidrug resistance after being modified on the gold nanoparticles by a reduction method, and the gold nanoparticles modified by the imidazole micromolecules have very good biocompatibility. Based on the invention, the research on the antibacterial property of the novel gold nanoparticles modified by similar molecules can be further explored to explore the rule and mechanism of the gold nanoparticles as the antibacterial agent, and in addition, the research on some molecules with poor biocompatibility can be avoided.
Drawings
Embodiments of the invention are described in detail below with reference to the attached drawing figures, wherein:
FIG. 1 shows a schematic diagram of a preparation method and an antibacterial effect of gold nanoparticles provided by the invention;
FIG. 2 shows cytotoxicity assessment of human umbilical vein endothelial cells at different concentrations of gold nanoparticles prepared in examples 2,4, 6, 8, 10 and 12;
FIGS. 3 to 14 show a scanning image and a particle size distribution of the gold nanoparticles prepared in examples 1 to 12, respectively, in a transmission electron microscope.
Detailed Description
The invention is further illustrated by the following specific examples, which, however, are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
This section generally describes the materials used in the testing of the present invention, as well as the testing methods. Although many materials and methods of operation are known in the art for the purpose of carrying out the invention, the invention is nevertheless described herein in as detail as possible. It will be apparent to those skilled in the art that the materials and methods of operation used in the present invention are well within the skill of the art, provided that they are not specifically illustrated.
The reagents and instrumentation used in the following examples are as follows:
reagent:
chloroauric acid, available from national drug group chemical reagents ltd; 3-amino-5-mercapto-1, 2, 4-triazole (ATT) was obtained from Bailingwei Tech, Beijing, 4-amino-3-hydrazine-5-mercapto-1, 2, 4-triazophos (AHMT) was obtained from Sahn Chemicals, Inc., 2-Mercaptoimidazole (MI) was obtained from Bailingwei Tech, Beijing, methimazole (MTM) was obtained from Sahn Chemicals, Inc., 2-amino-6-mercaptopurine (AMP) was obtained from Bailingwei Tech, and 6-amino-2-mercaptobenzothiazole (AMBT) was obtained from Yinaokai Tech, Beijing.
The instrument comprises the following steps:
transmission Electron Microscope (TEM), model Tecnai G220S-TWIN, FEI Inc., USA.
Microplate reader model Tecan infinite M200, TECAN.
Example 1
This example is provided to illustrate gold nanoparticles (ATT-Au) surface-modified with 3-amino-5-mercapto-1, 2, 4-triazole and a method for preparing the same according to the present invention.
The preparation method adopted in this embodiment can refer to the schematic diagram in fig. 1, and specifically includes:
(1) completely dissolving 3-amino-5-mercapto-1, 2, 4-triazole in methanol, and mixing with chloroauric acid to form a mixed solution, wherein the molar ratio of the 3-amino-5-mercapto-1, 2, 4-triazole to the chloroauric acid is shown in table 1.
(2) Stirring the mixed solution in the step (1) under an ice-bath magnetic stirrer, adding Tween 80, fully mixing and dissolving, adding sodium borohydride, and continuously stirring for 1 hour to obtain a gold nanoparticle crude product, wherein the molar ratio of the Tween 80 to the chloroauric acid and the molar ratio of the sodium borohydride to the chloroauric acid are shown in Table 1.
(3) Removing methanol by a rotary evaporator, adding a certain amount of distilled water to redissolve the gold nanoparticles, dialyzing the gold nanoparticles for 48 hours by using a dialysis bag with the density of 14KD, and collecting the gold nanoparticles and storing for later use.
The particle size of the gold nanoparticles is about 1-15 nm by TEM measurement, and the measurement result is shown in FIG. 3. And (3) determining by an X-ray energy spectrometer, wherein the molar ratio of the nitrogen heterocyclic micromolecules in the obtained gold nanoparticles to the gold is 0.36: 1.
Example 2
This example is provided to illustrate gold nanoparticles (ATT-Au) surface-modified with 3-amino-5-mercapto-1, 2, 4-triazole and a method for preparing the same according to the present invention.
The preparation method of this example is substantially the same as that of example 1 except that the preparation is performed according to the nitrogen heterocyclic small molecule, the molar ratio of the nitrogen heterocyclic small molecule to the chloroauric acid, the molar ratio of the tween 80 to the chloroauric acid, and the molar ratio of the sodium borohydride to the chloroauric acid, which are specified in the following table 1.
According to TEM measurement, the particle size of the gold nanoparticles is about 1-5 nm, and the measurement result is shown in FIG. 4. And (3) determining by an X-ray energy spectrometer, wherein the molar ratio of the nitrogen heterocyclic micromolecules in the obtained gold nanoparticles to the gold is 0.53: 1.
Example 3
This example is intended to illustrate the surface-modified 4-amino-3-hydrazine-5-mercapto-1, 2, 4-triazocene gold nanoparticles (AHMT-Au) of the present invention and the method for preparing the same.
The preparation method of this example is substantially the same as that of example 1 except that the preparation is performed according to the nitrogen heterocyclic small molecule, the molar ratio of the nitrogen heterocyclic small molecule to the chloroauric acid, the molar ratio of the tween 80 to the chloroauric acid, and the molar ratio of the sodium borohydride to the chloroauric acid, which are specified in the following table 1.
According to TEM measurement, the particle size of the gold nanoparticles is about 2-15 nm, and the measurement result is shown in FIG. 5. And (3) determining by an X-ray energy spectrometer, wherein the molar ratio of the nitrogen heterocyclic micromolecules in the obtained gold nanoparticles to the gold is 0.31: 1.
Example 4
This example is intended to illustrate the surface-modified 4-amino-3-hydrazine-5-mercapto-1, 2, 4-triazocene gold nanoparticles (AHMT-Au) of the present invention and the method for preparing the same.
The preparation method of this example is substantially the same as that of example 1 except that the preparation is performed according to the nitrogen heterocyclic small molecule, the molar ratio of the nitrogen heterocyclic small molecule to the chloroauric acid, the molar ratio of the tween 80 to the chloroauric acid, and the molar ratio of the sodium borohydride to the chloroauric acid, which are specified in the following table 1.
According to TEM measurement, the particle size of the gold nanoparticles is about 1-3 nm, and the measurement result is shown in FIG. 6. And (3) determining by an X-ray energy spectrometer, wherein the molar ratio of the nitrogen heterocyclic micromolecules in the obtained gold nanoparticles to the gold is 0.56: 1.
Example 5
This example is intended to illustrate the surface-modified 2-mercaptoimidazole gold nanoparticles (MI-Au) of the present invention and the method for preparing the same.
The preparation method of this example is substantially the same as that of example 1 except that the preparation is performed according to the nitrogen heterocyclic small molecule, the molar ratio of the nitrogen heterocyclic small molecule to the chloroauric acid, the molar ratio of the tween 80 to the chloroauric acid, and the molar ratio of the sodium borohydride to the chloroauric acid, which are specified in the following table 1.
According to TEM measurement, the particle size of the gold nanoparticles is about 2-35 nm, and the measurement result is shown in FIG. 7. And (3) determining by an X-ray energy spectrometer, wherein the molar ratio of the nitrogen heterocyclic micromolecules in the obtained gold nanoparticles to the gold is 0.34: 1.
Example 6
This example is intended to illustrate the surface-modified 2-mercaptoimidazole gold nanoparticles (MI-Au) of the present invention and the method for preparing the same.
The preparation method of this example is substantially the same as that of example 1 except that the preparation is performed according to the nitrogen heterocyclic small molecule, the molar ratio of the nitrogen heterocyclic small molecule to the chloroauric acid, the molar ratio of the tween 80 to the chloroauric acid, and the molar ratio of the sodium borohydride to the chloroauric acid, which are specified in the following table 1.
According to TEM measurement, the particle size of the gold nanoparticles is about 2-10 nm, and the measurement result is shown in FIG. 8. And (3) determining by an X-ray energy spectrometer, wherein the molar ratio of the nitrogen heterocyclic micromolecules in the obtained gold nanoparticles to the gold is 0.46: 1.
Example 7
This example is intended to illustrate the surface-modified methimazole gold nanoparticles (MTM-Au) of the present invention and the method for preparing the same.
The preparation method of this example is substantially the same as that of example 1 except that the preparation is performed according to the nitrogen heterocyclic small molecule, the molar ratio of the nitrogen heterocyclic small molecule to the chloroauric acid, the molar ratio of the tween 80 to the chloroauric acid, and the molar ratio of the sodium borohydride to the chloroauric acid, which are specified in the following table 1.
According to TEM measurement, the particle size of the gold nanoparticles is about 2-15 nm, and the measurement result is shown in FIG. 9. And (3) determining by an X-ray energy spectrometer, wherein the molar ratio of the nitrogen heterocyclic micromolecules in the obtained gold nanoparticles to the gold is 0.22: 1.
Example 8
This example is intended to illustrate the surface-modified methimazole gold nanoparticles (MTM-Au) of the present invention and the method for preparing the same.
The preparation method of this example is substantially the same as that of example 1 except that the preparation is performed according to the nitrogen heterocyclic small molecule, the molar ratio of the nitrogen heterocyclic small molecule to the chloroauric acid, the molar ratio of the tween 80 to the chloroauric acid, and the molar ratio of the sodium borohydride to the chloroauric acid, which are specified in the following table 1.
According to TEM measurement, the particle size of the gold nanoparticles is about 1-10 nm, and the measurement result is shown in FIG. 10. And (3) determining by an X-ray energy spectrometer, wherein the molar ratio of the nitrogen heterocyclic micromolecules in the obtained gold nanoparticles to the gold is 0.25: 1.
Example 9
This example is intended to illustrate the surface-modified 2-amino-6-mercaptopurine gold nanoparticles (AMP-Au) and the preparation method thereof according to the present invention.
The preparation method of this example is substantially the same as that of example 1 except that the preparation is performed according to the nitrogen heterocyclic small molecule, the molar ratio of the nitrogen heterocyclic small molecule to the chloroauric acid, the molar ratio of the tween 80 to the chloroauric acid, and the molar ratio of the sodium borohydride to the chloroauric acid, which are specified in the following table 1.
According to TEM, the particle size of the gold nanoparticles is about 2-10 nm, and the measurement result is shown in FIG. 11. And (3) determining by an X-ray energy spectrometer, wherein the molar ratio of the nitrogen heterocyclic micromolecules in the obtained gold nanoparticles to the gold is 0.30: 1.
Example 10
This example is intended to illustrate the surface-modified 2-amino-6-mercaptopurine gold nanoparticles (AMP-Au) and the preparation method thereof according to the present invention.
The preparation method of this example is substantially the same as that of example 1 except that the preparation is performed according to the nitrogen heterocyclic small molecule, the molar ratio of the nitrogen heterocyclic small molecule to the chloroauric acid, the molar ratio of the tween 80 to the chloroauric acid, and the molar ratio of the sodium borohydride to the chloroauric acid, which are specified in the following table 1.
The particle size of the gold nanoparticles is about 1-5 nm by TEM measurement, and the measurement result is shown in FIG. 12. And (3) determining by an X-ray energy spectrometer, wherein the molar ratio of the nitrogen heterocyclic micromolecules in the obtained gold nanoparticles to the gold is 0.40: 1.
Example 11
This example is intended to illustrate the surface-modified 6-amino-2-mercaptobenzothiazole gold nanoparticles (AMBT-Au) and the method of preparation thereof according to the present invention.
The preparation method of this example is substantially the same as that of example 1 except that the preparation is performed according to the nitrogen heterocyclic small molecule, the molar ratio of the nitrogen heterocyclic small molecule to the chloroauric acid, the molar ratio of the tween 80 to the chloroauric acid, and the molar ratio of the sodium borohydride to the chloroauric acid, which are specified in the following table 1.
The particle size of the gold nanoparticles is about 1-12 nm by TEM measurement, and the measurement result is shown in FIG. 13. The mole ratio of nitrogen heterocyclic micromolecules in the obtained gold nanoparticles to gold is 0.40:1 by the determination of an X-ray energy spectrum instrument.
Example 12
This example is intended to illustrate the surface-modified 6-amino-2-mercaptobenzothiazole gold nanoparticles (AMBT-Au) and the method of preparation thereof according to the present invention.
The preparation method of this example is substantially the same as that of example 1 except that the preparation is performed according to the nitrogen heterocyclic small molecule, the molar ratio of the nitrogen heterocyclic small molecule to the chloroauric acid, the molar ratio of the tween 80 to the chloroauric acid, and the molar ratio of the sodium borohydride to the chloroauric acid, which are specified in the following table 1.
The particle size of the gold nanoparticles is about 1-8 nm by TEM measurement, and the measurement result is shown in FIG. 14. And (3) determining by an X-ray energy spectrometer, wherein the molar ratio of the nitrogen heterocyclic micromolecules in the obtained gold nanoparticles to the gold is 0.92: 1.
TABLE 1
Examples 1 to 12 types of azacyclo small molecule, molar ratios of azacyclo small molecule to chloroauric acid, tween 80 to chloroauric acid, and sodium borohydride to chloroauric acid
Figure BDA0000997007500000121
Test example 1
The antibacterial effect of the gold nanoparticles prepared in examples 2,4, 6, 8, 10 and 12 was measured, which indicates that the gold nanoparticles have a good antibacterial effect.
The comparison method is as follows:
measured by minimum inhibitory concentration, the gramnegative bacteria and the related clinical isolates with multi-drug resistance are respectively cultured by a broth method to logarithmic phase, and then diluted to ensure that the number of bacteria used in the experiment is 104To 105Different strains were inoculated into 96-well plates at 100. mu.l per well. Adding synthesized different gold nanoparticles into the first hole of each strain from the original concentration, wherein the adding volume is 100 microliters, then diluting step by step, and taking only the strain as a blank control in the last hole, wherein all operations are carried out in a clean bench. And then placing the 96-well plate at 37 ℃ for constant-temperature culture for 24 hours, and evaluating the minimum inhibitory concentration of each different gold nanoparticle by observing the transparency of the well plate and a blank control. The test results are shown in Table 2.
As can be seen from the test results, the gold nanoparticles prepared in examples 2,4, 6, 8, 10 and 12 have good antibacterial effects against both gram-negative bacteria and drug-resistant gram-negative bacteria, and most of them also have good antibacterial effects against both gram-positive bacteria and drug-resistant gram-positive bacteria.
Table 2 antibacterial effect test of gold nanoparticles prepared in examples 2,4, 6, 8, 10 and 12
Figure BDA0000997007500000131
Test example 2 cytotoxicity test
Cytotoxicity experiments were performed on the gold nanoparticles prepared in examples 2,4, 6, 8, 10 and 12, and the cytotoxicity of the gold nanoparticles was evaluated.
The evaluation method is as follows:
inoculating human umbilical vein endothelial cells with good state in a 96-well plate, wherein 4 to 5 ten thousand cells are per well to ensure that the cell magnitude of each well is the same, culturing the well in a culture medium at 37 ℃ until the cells adhere to the wall, respectively adding different gold nanoparticles and diluting step by step, and performing no experimental treatment and only performing blank control on the periphery of the 96-well plate. After 24 hours of incubation at 37 ℃ in an incubator, the liquid is gently aspirated from each well, cck-8 reagent dye is added at 10 to 20 microliters, and incubation is carried out in an incubator for 2 to 4 hours until the color of the well plate changes significantly. The absorbance at 450nm was measured for each well in a 96-well plate using a microplate reader. Then calculating the cell activity of each hole by a calculation formula of the reagent method, thereby determining the toxicity of the corresponding gold nanoparticles to human umbilical vein endothelial cells. The test results are shown in FIG. 2.
As can be seen from the test results, even if the concentrations of the gold nanoparticles prepared in examples 6 and 8 are as high as 100 μ g/mL, the activities of the corresponding human umbilical vein endothelial cells are almost 100%, which indicates that the two gold nanoparticle concentrations have good biocompatibility. In addition, the gold nanoparticles prepared in example 12 all had higher cell activities than those prepared in the other examples to be evaluated except examples 6 and 8 at a concentration of 50. mu.g/mL or more.
Reagent kit
The present invention also provides a kit comprising the gold nanoparticles of the first aspect of the present invention or the gold nanoparticles prepared by the preparation method of the second aspect of the present invention.
In addition, instructions for use and/or use/analysis software may also be included in the kit.
Pharmaceutical composition
The invention also relates to an antibacterial pharmaceutical composition, which comprises a pharmaceutically acceptable carrier, and the gold nanoparticles of the first aspect of the invention or the gold nanoparticles prepared by the preparation method of the second aspect of the invention. The gold nanoparticles may be in an effective amount or a therapeutically effective amount in the pharmaceutical composition.
As used herein, "effective amount" refers to an amount that produces a function or activity in and is acceptable to humans and/or animals.
As used herein, a "pharmaceutically acceptable" component is one that is suitable for use in humans and/or animals (e.g., mammals and birds) without undue adverse side effects (such as toxicity, irritation, and allergic response), i.e., at a reasonable benefit/risk ratio. "pharmaceutically acceptable carrier" refers to a carrier for administration, and may include various excipients and diluents, and the like.
The pharmaceutical composition of the present invention may contain a safe and effective amount of the gold nanoparticles of the present invention as an active ingredient and a pharmaceutically acceptable carrier. Such vectors may include, but are not limited to: saline, buffer, glucose, water, glycerol, ethanol, and combinations thereof. The dosage form of the pharmaceutical composition of the present invention can be prepared into injections, oral preparations (tablets, capsules, oral liquids), transdermal agents, diluents, etc. as required. For example, it is usually prepared in a conventional manner using physiological saline or an aqueous solution containing glucose and other excipients. The pharmaceutical composition is preferably manufactured under sterile conditions.
The effective amount of the present invention may vary depending on the mode of administration and the severity of the disease to be treated, etc. The selection of a preferred effective amount can be determined by one of ordinary skill in the art based on a variety of factors (e.g., by clinical trials). Such factors include, but are not limited to: pharmacokinetic parameters of the active ingredient, such as bioavailability, metabolism, half-life, etc.; the severity of the disease to be treated by the patient, the weight of the patient, the immune status of the patient, the route of administration, and the like. In general, satisfactory results are obtained when the active ingredient of the invention is administered at a daily dose of about 0.00001mg to 50mg per kg of animal body weight (preferably 0.0001mg to 10mg per kg of animal body weight). For example, divided doses may be administered several times per day, or the dose may be proportionally reduced, as may be required by the urgency of the condition being treated.
The pharmaceutically acceptable carrier of the present invention includes, but is not limited to: water, saline, liposomes, lipids, proteins, protein-antibody conjugates, peptidic substances, cellulose, nanogels, or combinations thereof. The choice of carrier will generally be matched to the mode of administration, which is well known to those skilled in the art.
The invention also provides the application of the pharmaceutical composition in preparing an antibacterial product or preparing a medicament for preventing and/or treating diseases caused by microorganisms.
Prophylactic and/or therapeutic methods
The present invention also provides a method of preventing and/or treating a microorganism-caused disorder, the method comprising administering to a subject a therapeutically effective amount of the gold nanoparticles of the first aspect of the present invention, the gold nanoparticles prepared using the preparation method of the second aspect of the present invention, or the antimicrobial composition of the third aspect of the present invention.
Although the present invention has been described to a certain extent, it is apparent that appropriate changes in the respective conditions may be made without departing from the spirit and scope of the present invention. It is to be understood that the invention is not limited to the described embodiments, but is to be accorded the scope consistent with the claims, including equivalents of each element described.

Claims (21)

1. The application of gold nanoparticles in preparing antibacterial products or medicines for preventing and/or treating diseases caused by microorganisms is characterized in that the surfaces of the gold nanoparticles are modified with small nitrogen heterocyclic molecules; wherein the nitrogen heterocyclic small molecule is selected from one or more of triazole with sulfhydryl, imidazole with sulfhydryl, purine with sulfhydryl and benzothiazole with sulfhydryl.
2. The use according to claim 1, wherein the azacyclo small molecule is selected from one or more of 3-amino-5-mercapto-1, 2, 4-triazole, 4-amino-3-hydrazine-5-mercapto-1, 2, 4-triazocene, 2-mercaptoimidazole, methimazole, 2-amino-6-mercaptopurine and 6-amino-2-mercaptobenzothiazole.
3. Use according to claim 1, characterized in that:
the molar ratio of the nitrogen heterocyclic micromolecules to the gold element in the gold nanoparticles is 0.1-0.99: 1; and/or
The average particle size of the gold nanoparticles is 1-35 nm.
4. Use according to claim 3, characterized in that:
the molar ratio of the nitrogen heterocyclic micromolecules to the gold element in the gold nanoparticles is 0.22-0.92: 1; and/or
The average particle size of the gold nanoparticles is 2-10 nm.
5. Use according to claim 1, wherein the antimicrobial product is an antimicrobial agent or an antimicrobial pharmaceutical composition.
6. Use according to claim 5, wherein the antibacterial product or medicament is against one or more of the following bacterial species: gram-negative bacteria, gram-positive bacteria and clinical isolates with multidrug resistance, and/or
The microorganism-caused disease is caused by one or more of gram-negative bacteria, gram-positive bacteria and clinical isolates with multidrug resistance.
7. The use according to claim 6, wherein the gram-negative bacteria are selected from one or more of Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae,
the gram-positive bacteria are selected from Staphylococcus aureus, and/or
The clinical isolates with multidrug resistance are selected from one or more of multidrug resistant Escherichia coli, multidrug resistant Pseudomonas aeruginosa and multidrug resistant Staphylococcus aureus.
8. The use according to claim 6, wherein the condition is selected from one or more of: skin and subcutaneous tissue infections, wound infections, otitis media, meningitis, peritonitis, enteritis, bronchitis, pneumonia, respiratory tract infections, urinary system infections, sepsis or sepsis.
9. Use according to any one of claims 1 to 8, wherein the gold nanoparticles are prepared by a process comprising:
(1) dissolving the nitrogen heterocyclic micromolecules in methanol, mixing the dissolved nitrogen heterocyclic micromolecules with chloroauric acid to form mixed solution,
(2) adding a reducing agent into the mixed solution obtained in the step (1), fully reacting to obtain a gold nanoparticle crude product,
(3) and (3) purifying the gold nanoparticle crude product in the step (2) to obtain the gold nanoparticles.
10. The use according to claim 9, wherein the molar ratio of the nitrogen heterocyclic small molecule to the chloroauric acid in step (1) is 1-10: 1.
11. The use according to claim 10, wherein the molar ratio of the azacyclo small molecule to the chloroauric acid in step (1) is 10: 1.
12. The use according to claim 9, wherein after the mixing in step (1), the mixture is stirred and added with a nonionic surfactant or polyethylene glycol under ice bath conditions to mix them uniformly.
13. Use according to claim 12,
the non-ionic surfactant is selected from Triton X-100 or Tween; and/or
The molar ratio of the nonionic surfactant to the chloroauric acid is 0.1-2: 1.
14. Use according to claim 13,
the non-ionic surfactant is tween 80; and/or
The molar ratio of the nonionic surfactant to the chloroauric acid is 0.5-1.5: 1.
15. The use according to claim 9, wherein the reducing agent in step (2) is selected from one or more of sodium borohydride, sodium ascorbate and sodium citrate;
the molar ratio of the reducing agent to the chloroauric acid is 1-10: 1; and/or
The reaction was carried out in an ice bath with stirring.
16. The use according to claim 15, wherein the reducing agent in step (2) is sodium borohydride;
the molar ratio of the reducing agent to the chloroauric acid is 2-8: 1; and/or
The reaction time is 30 minutes to 2 hours.
17. Use according to claim 16,
the molar ratio of the reducing agent to the chloroauric acid is 3: 1; and/or
The reaction time was 1 hour.
18. Use according to claim 9, wherein the purification in step (3) comprises removing methanol.
19. Use according to claim 18, wherein the removal of methanol in step (3) is carried out by means of a rotary evaporator.
20. The use of claim 19, wherein the purification further comprises dialysis.
21. The use according to claim 20,
the dialysis adopts a 14KD dialysis bag for 48 hours; and/or
And adding distilled water to the gold nanoparticles from which the methanol is removed to dissolve the gold nanoparticles, and then dialyzing.
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